There is a marked variability in the period of latency between infection by HIV- l and the onset of AIDS. The latency period is determined by host factors that control viral infectivity. Chemokine receptors (CCR5 and CXCR4) serve as co-receptors for HIV-1 entry into cells. The pivotal role of the interactions between HIV-1 and chemokine receptor was realized with epidemiological data clearly demonstrating that individuals expressing mutant CCR5 receptors had a slower progression of their HIV-1 infection. We provide preliminary data indicating that IgM autoantibodies that bind to CCR5 and CXCR4 on lymphocytes are present in normal human serum. Futhermore, our preliminary studies show that IgM anti-lymphocyte antibodies obtained from normal individuals or asymptomatic HIV-1 infected individuals significantly inhibits HIV-1 from infecting cells. We have shown that this subset of IgM antilymphocyte autoantibodies with HIV-1 inhibitory activity is depleted in patients with AIDS. At this stage, it is unclear whether the subset of IgM anti-lymphocyte antibody with HIV-1 inhibitory activity is predominantly the antibody that binds to chemokine receptors on the lymphocyte or whether this HIV-1 inhibitory subset in addition consists of other antibodies binding to non-chemokine receptors, e.g. to CD4. These IgM anti-CCR5 and CXCR4 autoantibodies do not significantly inhibit chemotaxis even though they partially inhibit chemokines from binding to the receptors. In the proposed in-vitro studies, we plan to focus on human IgM anti-lymphocyte autoantibodies to better characterize the subset of anti-lymphocyte antibodies that prevent HIV-1 from infecting susceptible cells. (i) Human B lymphocytes will be transformed with EBV virus in an effort to find B cell clones secreting IgM that bind to lymphocytes and inhibit HIV-1 infectivity. Each clone will be evaluated for their range of inhibitory activity towards a defined panel of different HIV-1 strains. Several of the monoclonal IgM clones with HIV-1 inhibitory activity will be further evaluated for their binding specificity and affinity to chemokine receptors and CD4 receptors and their effect on chemotaxis. (ii) We will also determine if there are HIV-1 inhibitory clones secreting IgM that has no binding activity to chemokine receptors. A successful outcome with the proposed studies could better our understanding on pathogenesis of H1V-1 infection and may provide strategies to prolong the asymptomatic state after HIV-1 infection.